title: STAT1 negatively regulates spatial memory formation and mediates the memory-impairing effect of Aβ.
abstract: Signal transducer and activator of transcription-1 (STAT1) has an important role in inflammation and the innate immune response, but its role in the central nervous system is less well understood. Here, we examined the role of STAT1 in spatial learning and memory, and assessed the involvement of STAT1 in mediating the memory-impairing effect of amyloid-beta (Aβ). We found that water maze training downregulated STAT1 expression in the rat hippocampal CA1 area, and spatial learning and memory function was enhanced in Stat1-knockout mice. Conversely, overexpression of STAT1 impaired water maze performance. STAT1 strongly upregulated the expression of the extracellular matrix protein laminin β1 (LB1), which also impaired water maze performance in rats. Furthermore, Aβ impaired spatial learning and memory in association with a dose-dependent increase in STAT1 and LB1 expression, but knockdown of STAT1 and LB1 both reversed this effect of Aβ. This Aβ-induced increase in STAT1 and LB1 expression was also associated with a decrease in the expression of the N-methyl-D-aspartate receptor (NMDAR) subunits, NR1, and NR2B. Overexpression of NR1 or NR2B or exogenous application of NMDA reversed Aβ-induced learning and memory deficits as well as Aβ-induced STAT1 and LB1 expression. Our results demonstrate that STAT1 negatively regulates spatial learning and memory through transcriptional regulation of LB1 expression. We also identified a novel mechanism for Aβ pathogenesis through STAT1 induction. Notably, impairment of spatial learning and memory by this STAT1-mediated mechanism is independent of cAMP responsive element-binding protein signaling.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Wei-Lun
authors.initials: WL
authors.lastname: Hsu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Yun-Li
authors.initials: YL
authors.lastname: Ma
authors.affiliation: 1] Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan [2] Institute of Neuroscience, National Cheng-chi University, Taipei, Taiwan.
authors.forename: Ding-You
authors.initials: DY
authors.lastname: Hsieh
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Yen-Chen
authors.initials: YC
authors.lastname: Liu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Eminy Hy
authors.initials: EH
authors.lastname: Lee
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000172:deficiency* / Q000235:genetics; D013028:Space Perception / Q000187:drug effects* / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; C513277:Lamb1 protein, mouse; D007797:Laminin; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate; D050794:STAT1 Transcription Factor; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D050882:CREB-Binding Protein